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Automated docking in crystallography: analysis of the substrates of aconitase.
Proteins. 1993 Sep; 17(1):1-10.P

Abstract

Automated docking of substrates to proteins of known structure aids the process of crystallographic analysis in two ways. First, automated docking can be used to generate a small number of starting models for substrates using only protein coordinates from an early stage of refinement. Second, automated docking provides a method for exploring aspects of catalysis that are inaccessible to crystallography by postulating binding modes of catalytic intermediates. This paper describes the use of automated docking to explore the binding of substrates to aconitase. The technique starts with a substrate molecule in an arbitrary configuration and position and finds favorable docked configurations in a (static) protein active site based on a molecular mechanics type force field. Using protein coordinates from an early stage of refinement of an aconitase-isocitrate complex, we successfully predicted the binding configuration of isocitrate. Four configurations were found, the energetically most favorable of which fit the observed electron density well and was used as a starting model for further refinement. Two configurations were found in citrate docking experiments, the second of which approximates the mode of substrate binding in an aconitase-nitrocitrate complex. We were also able to propose two binding modes of the catalytic intermediate cis-aconitate. These correspond closely to the isocitrate and the citrate binding modes. The relation of these new results to the proposed reaction mechanism is discussed.

Authors+Show Affiliations

Goodsell DS
Molecular Biology Institute, University of California, Los Angeles 90024.
Lauble H
No affiliation info available
Stout CD
No affiliation info available
Olson AJ
No affiliation info available

MeSH

Aconitate HydrataseAconitic AcidBinding SitesCitratesCitric AcidCrystallographyIsocitratesModels, ChemicalModels, MolecularSubstrate Specificity

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8234239

Citation

Goodsell, D S., et al. "Automated Docking in Crystallography: Analysis of the Substrates of Aconitase." Proteins, vol. 17, no. 1, 1993, pp. 1-10.
Goodsell DS, Lauble H, Stout CD, et al. Automated docking in crystallography: analysis of the substrates of aconitase. Proteins. 1993;17(1):1-10.
Goodsell, D. S., Lauble, H., Stout, C. D., & Olson, A. J. (1993). Automated docking in crystallography: analysis of the substrates of aconitase. Proteins, 17(1), 1-10.
Goodsell DS, et al. Automated Docking in Crystallography: Analysis of the Substrates of Aconitase. Proteins. 1993;17(1):1-10. PubMed PMID: 8234239.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Automated docking in crystallography: analysis of the substrates of aconitase. AU - Goodsell,D S, AU - Lauble,H, AU - Stout,C D, AU - Olson,A J, PY - 1993/9/1/pubmed PY - 1993/9/1/medline PY - 1993/9/1/entrez SP - 1 EP - 10 JF - Proteins JO - Proteins VL - 17 IS - 1 N2 - Automated docking of substrates to proteins of known structure aids the process of crystallographic analysis in two ways. First, automated docking can be used to generate a small number of starting models for substrates using only protein coordinates from an early stage of refinement. Second, automated docking provides a method for exploring aspects of catalysis that are inaccessible to crystallography by postulating binding modes of catalytic intermediates. This paper describes the use of automated docking to explore the binding of substrates to aconitase. The technique starts with a substrate molecule in an arbitrary configuration and position and finds favorable docked configurations in a (static) protein active site based on a molecular mechanics type force field. Using protein coordinates from an early stage of refinement of an aconitase-isocitrate complex, we successfully predicted the binding configuration of isocitrate. Four configurations were found, the energetically most favorable of which fit the observed electron density well and was used as a starting model for further refinement. Two configurations were found in citrate docking experiments, the second of which approximates the mode of substrate binding in an aconitase-nitrocitrate complex. We were also able to propose two binding modes of the catalytic intermediate cis-aconitate. These correspond closely to the isocitrate and the citrate binding modes. The relation of these new results to the proposed reaction mechanism is discussed. SN - 0887-3585 UR - https://www.unboundmedicine.com/medline/citation/8234239/Automated_docking_in_crystallography:_analysis_of_the_substrates_of_aconitase_ L2 - https://doi.org/10.1002/prot.340170104 DB - PRIME DP - Unbound Medicine ER -